Cardiac output (CO) is the volume of blood ejected by the heart per unit time, while left atrial pressure (LAP) generally indicates the blood pressure attained in the left ventricle during the filling phase of the cardiac cycle. CO and LAP are perhaps the two most important quantities to be able to monitor in critically ill patients, as they facilitate the diagnosis, monitoring, and treatment of various disease processes such as left ventricular failure, mitral valve disease, and shock of any cause [36]. For example, a decrease in CO while LAP is rising would indicate that the patient is in left ventricular failure, whereas a decrease in CO while LAP is falling would indicate that the patient might be going into hypovolemic shock.
Several methods are currently available for monitoring CO or LAP. While each of these methods can offer some advantages, as described below, all of the methods are limited in at least one clinically significant way.
The standard methods intended for monitoring CO and LAP in critically ill patients both involve the use of the balloon-tipped, flow-directed pulmonary artery catheter [47,70]. This catheter also permits continuous monitoring of pulmonary artery pressure (PAP) and central venous pressure (i.e., right ventricular filling pressure) via fluid-filled systems attached to external pressure transducers. (However, the most common reason for inserting the pulmonary artery catheter is perhaps in an effort to monitor LAP [46].) CO is specifically estimated according to the thermodilution method [17,47]. This method involves injecting a bolus of cold saline in the right atrium, measuring temperature downstream in the pulmonary artery, and computing the average CO based on conservation laws. LAP is estimated through pulmonary capillary wedge pressure (PCWP), which is determined by advancing the catheter into a branch of the pulmonary artery, inflating the balloon, and averaging the ensuing steady-state pressure [47].
Since PCWP is measured when flow has ceased through the branch, in theory, the PCWP should provide an estimate of LAP. However, the PCWP is not equal to LAP and is only an approximation [31,44]. In fact, as a result of a number of technical problems, in practice, the PCWP method frequently provides only a poor estimate of LAP. These problems include partial wedging and balloon over-inflation [38,53], dependence of the measurement on the wedge catheter position [27,33], and inter-clinician variability in interpreting the phasic PCWP measurement [37]. Indeed, the developers of the PCWP method and the balloon-tipped, flow-directed catheter each reported that they could satisfactorily measure PCWP only about three quarters of the time [58,70]. In 2,711 PCWP measurement attempts made in the ICU, Morris et al reported that only 69% of these attempts were successful with only 10% of the unsatisfactory measurements due to easily correctable damped tracings [53]. Similar technical problems are also encountered in implementing the thermodilution method in which variations in injectate volume, rate, and temperature introduce error in the measurement, which is known to be in the 15-20% range [39,50,68]. Also, the very injection of fluid and balloon inflation poses some risk to the patient [17,34,42]. Perhaps, as a result of these shortcomings, the clinical benefit of the pulmonary artery catheter has yet to be clearly established (e.g., [64]). In addition, a major limitation of the thermodilution and PCWP methods is that an operator is required. Thus, these important measurements are only made every few hours.
Alternative methods for monitoring CO include the aortic flow probe, oxygen Fick, dye-dilution, continuous thermodilution, Doppler ultrasound, and thoracic bioimpedance. The aortic flow probe uses ultrasound transit-time (or electromagnetic) principles to measure instantaneous flow [17]. While this method is continuous and very accurate, it requires the placement of the flow probe directly around the aorta and is therefore much too invasive for most clinical applications. The oxygen Fick method involves simultaneous measurement of central venous and arterial oxygen content of blood and measurement of ventilatory oxygen uptake [17]. Although this method is also highly regarded in terms of its accuracy, it is too cumbersome for frequent clinical application. The dye dilution method involves the injection of a dye into the right atrium and serial measurement of the dye concentration in blood samples drawn from an arterial catheter [17]. The related thermodilution method is generally preferred over this method, because thermodilution requires only one catheter and is less affected by indicator recirculation. The continuous thermodilution method involves automatic heating of blood in the right atrium via a thermal filament, measurement of the temperature changes downstream in the pulmonary artery, and computation of average flow via cross correlation and bolus thermodilution principles [17,76]. While this method does not require an operator, the temperature changes generated by the thermal filament must be small to avoid damaging tissue and blood [17]. As a result, the signal to noise ratio of continuous thermodilution is small compared to standard thermodilution, which may render the continuous approach to be less accurate [78]. Doppler ultrasound methods generally measure the Doppler shift in the frequency of an ultrasound beam reflected from the flowing aortic blood [17]. These non-invasive methods are not commonly employed in critical care medicine, because they require expensive capital equipment and an expert operator to stabilize an external ultrasound transducer [40]. Thoracic bioimpedance involves measuring changes in the electrical impedance of the thorax during the cardiac cycle [17,40]. Although this method is non-invasive and continuous, it is too inaccurate for use in critically ill patients due to excessive lung fluids [11].
Alternative methods for monitoring LAP include direct left heart catheterization, physical examination, and Doppler imaging. Direct catheterization of the left heart is the gold standard method permitting continuous and accurate monitoring of LAP [65]. However, this method is too invasive and risky for routine clinical application. In a physical examination, clinical and radiographic signs of congestion such as rales, third heart sound, prominent jugular vein, and interstitial and alveolar edema are utilized to obtain a qualitative indication of elevated LAP in patients typically with heart failure [9]. While this approach is simple and non-invasive, it is neither continuous nor has it been shown to be sensitive to at least changes in PCWP [9,16,69]. In Doppler imaging methods (e.g., color M-mode Doppler, tissue Doppler, pulsed Doppler), parameters such as transmitral and pulmonary venous velocity profiles are obtained to qualitatively monitor LAP changes or quantitatively monitor PCWP through empirical formulas [21,22,57]. Although these techniques may also be non-invasive, they are expensive, can only be used intermittently, and are not specific and may therefore be inaccurate [2,57, 62].
It would be desirable to be able to accurately monitor both CO and LAP by analysis of a PAP waveform, a right ventricular pressure (RVP) waveform, or other circulatory signals. Thus, unlike the aforementioned methods, this approach would permit continuous and automatic measurement of these two critically important hemodynamic variables with a level of invasiveness suitable for routine clinical use. A continuous and automatic monitoring approach would be desirable for several reasons. Continuous monitoring of both CO and LAP would be a great advantage during fluid and pharmaceutical interventions, as the clinician would be able to assess the effects of the interventions and be quickly alerted to possible complications. Continuous monitoring would also provide an early indication of deleterious hemodynamic events induced by disease (e.g., hypovolemia via simultaneously decreasing CO and LAP). Moreover, automatic monitoring would save precious time in the busy intensive care unit (ICU) and operating room (OR) environments [17] and circumvent the clinically significant problems associated with implementing the standard measurement methods (see above). Finally, the approach would be a tremendous advantage in the context of remote ICU monitoring (e.g., [63]) and ambulatory monitoring of PAP or RVP waveforms (in, for example, heart failure patients) via available implanted devices [1,67]. A method for such chronic monitoring of both of these two valuable hemodynamic variables does not otherwise exist.
Many investigators have sought analysis techniques to continuously monitor CO from arterial pressure waveforms. Such techniques have been proposed for over a century [19].
Much of the earlier work assumed that either arterial tree is well represented by a Windkessel model accounting for the compliance of the large arteries and the vascular resistance of the small arteries. FIG. 1 illustrates the electrical analog of a Windkessel model of the systemic arterial tree. (Because systemic vascular resistance (SVR) is relatively large, the model here assumes that the systemic venous pressure (SVP) is negligible with respect to the systemic arterial pressure (SAP) by virtue of SVR being referenced to atmospheric pressure rather than SVP.) While techniques based on this simple model generally failed when applied to SAP waveforms measured centrally in the aorta (e.g., [66,72]), Bourgeois et al showed that their technique yielded a quantity that varied linearly with aortic flow probe CO over a wide physiologic range [6]. The key concept of their technique is that, according to the Windkessel model, SAP should decay like a pure exponential during each diastolic interval with a time constant (τ) equal to the product of SVR and systemic arterial compliance (AC). Since AC is nearly constant over a wide pressure range and on the time scale of months [5,26,60], CO could then be measured to within a constant scale factor by dividing the time-averaged SAP with τ. Thus, the technique of Bourgeois et al involves fitting an exponential function to each diastolic interval of a SAP waveform to measure τ (FIG. 1).
Bourgeois et al were able to validate their technique with respect to central SAP waveforms, because the diastolic interval of these waveforms can sometimes resemble an exponential decay following incisura (FIG. 2a). These investigators identified a precise location in the thoracic aorta as the optimal site in the canine for observing an exponential diastolic decay. However, central SAP is rarely measured clinically due to the risk of blood clot formation and embolization. Moreover, exponential diastolic decays are usually not apparent in either peripheral SAP waveforms (FIG. 2b), which may be measured via minimally invasive radial artery catheterization, or PAP waveforms (FIG. 2c). Indeed, Bourgeois et al acknowledged that exponential diastolic decays are obscured in peripheral SAP waveforms [5]. Moreover, after Engelberg et al suggested that the pulmonary arterial tree be represented by a Windkessel model in which the small pulmonary vascular resistance (PVR) is referenced to LAP (electrical analog in FIG. 3) [18], Milnor et al attempted to fit an exponential function to each diastolic decay interval of PAP waveforms minus average LAP in man and reported that all of the waveforms were not adequate for doing so [51]. Subsequently, Tajimi et al reported that they were not able to identify a location in the canine or human pulmonary artery in which exponential diastolic pressure decays were consistently visible [71]. The reason is that the systemic and pulmonary arterial trees are not simply lumped systems like the Windkessel model suggests but rather complicated distributed systems with impedance mismatches throughout due to vessel tapering, bifurcations, and caliber changes. The diastolic (and systolic) intervals of peripheral SAP and PAP waveforms are therefore corrupted by complex wave reflections occurring at each and every site of impedance mismatch. Moreover, inertial effects also contribute to obscuring exponential diastolic decays, especially in the low-pressure pulmonary arterial tree [55]. Thus, the technique of Bourgeois et al cannot be applied to clinically measurable peripheral SAP and PAP waveforms.
More recently, investigators have attempted to monitor CO from peripheral SAP waveforms. Techniques based on an adaptive aorta model, which require SAP waveforms measured at both the carotid and femoral arteries have been proposed [59,73]. However, catheters are usually not placed for prolonged periods of time at either of these sites in ICUs, ORs, or recovery rooms due to safety considerations. A technique has been introduced that is based on an empirically derived formula involving the calculation of the derivative of the ABP waveform [23]. However, in order to mitigate the corruptive effects of wave reflections on the derivative calculation, this technique also requires two peripheral ABP measurements, one of which is obtained from the femoral artery. Learning techniques requiring training data sets consisting of simultaneous measurements of CO and SAP waveforms have also been suggested [8,24,48]. However, these techniques were only demonstrated to be successful in central ABP waveforms or over a narrow physiologic range. Moreover, learning techniques could only be successful provided that the available training set of patient data reflected the entire patient population. Finally, Wesseling et al [3,74] and Linton et al [41] have proposed techniques requiring only the analysis of a single radial SAP waveform. However, Linton et al only showed that their technique was accurate over a narrow physiologic range, and several studies have demonstrated limitations of the technique of Wesseling et al (e.g., [20,29]).
A technique for continuous CO monitoring from peripheral SAP waveforms has been the recent focus of interest, because it is minimally invasive or possibly even non-invasive (e.g., [24]). However, even if such a technique were introduced with sufficient accuracy, the more invasive pulmonary artery catheters would still be used to be able to measure left and right ventricular filling pressures. Four investigators have therefore previously attempted to monitor CO continuously by analysis of PAP waveforms [10,15,71,77]. In this way, ventricular filling pressures and continuous CO could be measured with a single catheter. These investigators essentially employed analysis techniques that were previously applied to SAP waveforms. Their results showed that the techniques could estimate CO during cardiac interventions but not vascular interventions (e.g., volume infusion). Moreover, even though LAP is also a significant determinant of PAP and should therefore be reflected in the PAP waveform, none of these techniques included a means to monitor LAP. In fact, similar to the suggestion of Engelberg et al, the technique of Cibulski et al actually required an additional LAP measurement for monitoring CO [10].
The common feature of all of the aforementioned techniques for monitoring CO from continuous SAP or PAP is that the waveform analysis is employed only over time scales within a cardiac cycle. Because of the corruptive effects of highly complex waves at these time scales, the techniques were limited in that they 1) could only be applied to highly invasive central SAP waveforms in which the complex wave reflections may be attenuated; 2) necessitated multiple peripheral SAP waveform measurements (which are rarely obtained clinically); 3) required an exhaustive training data set, and/or 4) are accurate only over a narrow physiologic range or only during cardiac interventions. However, the confounding effects of wave as well as inertial phenomenon are known to diminish with increasing time scale [55]. Based on this under-appreciated concept, Mukkamala et al introduced a technique to monitor CO by analyzing a single arterial pressure waveform (measured at any site in the systemic or pulmonary arterial trees) over time scales greater than a cardiac cycle [54]. They evaluated their technique with respect to peripheral SAP waveforms in swine and their results showed excellent agreement with aortic flow probe measurements over a wide physiologic range [54]. While this technique may permit continuous and accurate monitoring of CO with a level of invasiveness suitable for routine clinical application, it does not provide a convenient means to monitor LAP.
Some investigators have attempted to monitor LAP or PCWP by analysis of blood pressure waveforms. Shortly after the introduction of the pulmonary artery catheter, researchers studied the end-diastolic PAP as a continuous index of LAP [28,31]. However, this simple technique is not as accurate as the PCWP method [31] (see below) and becomes unreliable when the rate of drainage of blood from the pulmonary artery into the pulmonary capillaries is slow. Thus, for example, it is well known that the end-diastolic PAP is not an acceptable index of LAP in patients with pulmonary vascular disease [28]. More recently, a learning technique has been proposed to monitor PCWP from a PAP waveform using an artificial neural network trained on a database of PCWP measurements and PAP waveforms [14, 78]. However, this technique was shown to be ineffective when the network was trained on one set of subjects and tested on a different set of subjects [14]. Finally, techniques have been proposed in which trained regression equations predict LAP or PCWP from variations in parameters of the SAP or plethysmographic waveform (e.g., systolic pressure, pulse pressure) in response to the Valsalva maneuver or mechanical positive pressure ventilation [45,49,65,75]. While these techniques may be minimally invasive or non-invasive, they are either not continuous or applicable to subjects breathing spontaneously. Moreover, since SAP and related signals are also due to ventricular and arterial functionality, these techniques do not provide a specific measure of LAP or PCWP and may therefore be inaccurate [13].
Thus, a technique is needed that accurately monitors both CO and LAP by analysis of a PAP waveform, a RVP waveform, or other circulatory signals. Such a technique could be utilized, for example, to continuously monitor critically ill patients instrumented with pulmonary artery catheters and chronically monitor heart failure patients instrumented with implanted devices.